Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor

Tse, Kam Fai; Novelli, Enrico M.; Civin, Curt I.; Böhmer, Frank D.; Small, Donald

doi:10.1038/sj.leu.2402199

Cited by 112 publications

(89 citation statements)

References 67 publications

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“…The first FLT3 inhibitors to be identified were the tyrphostins AG1295 and AG1296. 90,138,139 These compounds, originally characterized as PDGF-R inhibitors, 140 inhibit FLT3 autophosphorylation in vitro (each with an IC 50 of 300 nM), and are cytotoxic to FLT3-dependent cell lines at doses that correspond to the inhibition of FLT3 autophosphorylation. Furthermore, AG1295 was selectively cytotoxic to primary AML blasts harboring FLT3/ITD mutations, a finding that further validates FLT3 as a therapeutic target.…”

Section: Flt3 Inhibitorsmentioning

confidence: 99%

“…79 A number of additional small-molecule tyrosine kinase inhibitors with activity against FLT3 have now been identified (Table 5). 79,108,112,138,139,[141][142][143][144][145][146] These FLT3 inhibitors encompass a variety of chemical classes, but all are heterocyclic compounds containing a structural mimic of the purine component of ATP. While direct structural analysis of FLT3 is not yet available, analysis of the crystal structure data for a variety of other kinases bound to different small-molecule inhibitors allows some deductions to be made regarding the structure activity relationships of FLT3 inhibitors.…”

Section: Flt3 Inhibitorsmentioning

confidence: 99%

“…They likewise induce apoptosis in murine 32D and Ba/F3 cells transfected with FLT3/ITD constructs, and are selectively (Table 5). 79,90,138,139,[149][150][151][152] Two of these, the indolocarbazole derivatives CEP-701 and PKC412, have been entered into phase II studies of relapsed and refractory AML patients with FLT3 activating mutations. The early results, presented in abstract form at the December 2002 American Society of Hematology meeting, were encouraging.…”

Section: Flt3 Inhibitorsmentioning

confidence: 99%

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FLT3: ITDoes matter in leukemia

2003

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FMS-like tyrosine kinase-3 (FLT3), a receptor tyrosine kinase, is important for the development of the hematopoietic and immune systems. Activating mutations of FLT3 are now recognized as the most common molecular abnormality in acute myeloid leukemia, and FLT3 mutations may play a role in other hematologic malignancies as well. The poor prognosis of patients harboring these mutations renders FLT3 an obvious target of therapy. This review summarizes the data on the molecular biology and clinical impact of FLT3 mutations, as well as the therapeutic potential of several small-molecule FLT3 inhibitors currently in development.

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Section: Flt3 Inhibitorsmentioning

confidence: 99%

Section: Flt3 Inhibitorsmentioning

confidence: 99%

Section: Flt3 Inhibitorsmentioning

confidence: 99%

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FLT3: ITDoes matter in leukemia

2003

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“…Several small-molecule inhibitors block the kinase activity of FLT3 with high potency [10][11][12][13] (eg, PKC412, MLN518, SU11248) and can prolong the lifespans of mice harboring leukemias expressing mutant FLT3 receptors. 10,14 In phase-1 and -2 clinical trials, FLT3 inhibitors have reduced FLT3 phosphorylation [15][16][17] and leukemia blast counts and have induced clinical responses in patients with advanced therapy-refractive AML.…”

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confidence: 99%

Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Jiang

Páez

Lee

et al. 2004

Blood

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The FLT3 receptor is activated by juxtamembrane insertion mutations and by activation loop point mutations in patients with acute myeloid leukemia (AML). In a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons were sequenced in samples from 53 patients with AML, 9 patients with acute lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three patients had novel point mutations at residue N841 that resulted in a change to isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I cDNA into Ba/F3 cells led to interleukin-3 (IL-3)-independent proliferation, receptor phosphorylation, and constitutive activation of signal transducer and activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK), suggesting that the N841I mutation confers constitutive activity to the receptor. An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC 50 10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced tyrosine phosphorylation of the mutant receptor and inhibited STAT5 phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841 is the key residue in a hydrogen-bonding network that likely stabilizes the activation loop. These results suggest that mutations at N841 represent a significant new activating mutation in patients with AML and that patients with such mutations may respond to smallmolecule FLT3 inhibitors such as PKC412. IntroductionFLT3, a class 3 receptor tyrosine kinase, is targeted and activated by somatic mutation in acute myeloid leukemia (AML). Internal tandem duplication (ITD) mutations of the FLT3 juxtamembrane (JM) occur in approximately 24% of patients with AML and in 15% of patients with secondary AML 1,2 and are associated with shortened disease-free survival. 3 Mutations in the activation loop (AL), typically D835Y, occur in approximately 7% of patients with AML and 3% of patients with myelodysplastic syndromes (MDS) 4,5 and in patients with T-cell ALL (T-ALL). 6 An increased frequency of FLT3 mutations has also been associated with mutations involving the mixed-lineage leukemia (MLL) gene. 7 ITD and AL mutations result in constitutive FLT3 kinase activity. When FLT3 receptors harboring such mutations are introduced into mammalian cells, downstream signaling pathways are activated that lead to factor-independent growth in vitro and to leukemogenesis in vivo. 8,9 For example, the production of FLT3-ITD mutant proteins in primary murine bone marrow cells results in a lethal myeloproliferative phenotype. 10 Thus, FLT3 is a leukemia oncogene, and activating FLT3 mutations likely contribute significantly to the development of leukemia in humans.Several small-molecule inhibitors block the kinase activity of FLT3 with high potency 10-13 (eg, PKC412, MLN518, SU11248) and can prolong the lifespans of mice harboring leukemias expressing mutant FLT3 receptors. 10,14 In phase-1 and -2 clinical trials, FLT3 inhibitors have reduced FLT3 phosphorylation 15-17 and leukemia...

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“…Published reports indicate that FLT-3 inhibitors kill cell lines and primary AML cells that are dependent upon expression of mutant FLT-3 for growth. [8][9][10][11] Some 20-30% of AML patients have leukemic cells that have an FLT-3 mutation; these proteins may be viable targets in AML, unlike c-kit, which is rarely mutated. FLT-3 is necessary for the development of hematopoietic and immune cells (natural killer cells and dendritic cells).…”

mentioning

confidence: 99%

Induction and postremission therapy: new agents

Stone

2003

Leukemia

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Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor

Cited by 112 publications

References 67 publications

FLT3: ITDoes matter in leukemia

FLT3: ITDoes matter in leukemia

Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Induction and postremission therapy: new agents

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